human psychopharmacology Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. Published online 3 December 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2369
A meta-analysis of inositol for depression and anxiety disorders Tomohiko Mukai†, Taro Kishi*,†, Yuki Matsuda and Nakao Iwata Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
Objective This study is a meta-analysis of inositol as a treatment for depression and anxiety disorders. Methods PubMed, Cochrane Library database, and PsycINFO were searched up to 14 August 2013. A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials (RCTs) were conducted comparing inositol for depressed or anxiety disorder patients. Results Seven RCTs in depression (two bipolar depression studies, one bipolar depression and major depressive disorder (MDD) study, two MDD studies, and two premenstrual dysphoric disorder (PMDD) studies) (n = 242) were identified. Four RCTs in anxiety disorders (two obsessive–compulsive disorder studies, one panic disorder study, and one posttraumatic stress disorder study) (n = 70) were also identified. There were no statistically significant effects of inositol on depressive, anxiety, and obsessive–compulsive symptoms and discontinuation (all-cause, side effects, and worsening psychiatric symptoms). However, inositol had marginally more responders in depression than placebo (p = 0.06), and inositol showed a trend towards superior efficacy for depressive symptoms in patients with PMDD (p = 0.07). Inositol marginally caused gastrointestinal upset compared with placebo (p = 0.06). Conclusions Our results suggest that inositol may be beneficial for depressed patients, especially those with PMDD. The main limitation of this report is that a small number of studies were included in this meta-analysis. Copyright © 2013 John Wiley & Sons, Ltd. key words—inositol; major depressive disorder; bipolar depression; premenstrual dysphoric disorder; anxiety disorder; meta-analysis
INTRODUCTION Inositol has been reported to be effective for the treatment of depressed patients (Benjamin et al., 1995a). Inositol is naturally found in a variety of foods and is a vitamin-like substance that is present in all animal tissues (the highest concentrations are found in the heart and brain). Inositol is a constituent of the intracellular phosphatidyl inositol second messenger system, which is linked to various neurotransmitter receptors, such as serotonin, dopamine, and glutamate receptor, thereby altering brain neurotransmitters including serotonin level (Benjamin et al., 1995a, Camfield et al., 2011). This accumulated evidence supports the indoleamine hypothesis of depression, which suggests that major depression results from inefficient serotonin or deficient amounts of available serotonin (Albert and Benkelfat, 2013, Albert et al., 2012). In addition, several lines of evidence implicate abnormalities in glutamate neural transmission in the pathophysiology of depression (i.e., the glutamate hypothesis of depression). When postmortem brain tissues were examined from depressed patients, low *Correspondence to: T. Kishi, Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan. E-mail: [email protected] † These authors contributed equally to this work.
Copyright © 2013 John Wiley & Sons, Ltd.
inositol levels were found in the frontal cortex (Coupland et al., 2005, Shimon et al., 1997). In addition, Barkai and colleagues found reduced levels of inositol in the cerebrospinal fluid of depressed patients (Barkai et al., 1978). Taylor and colleagues reported that inositol did not show clear evidence of a therapeutic benefit in depressed patients (four studies, n = 141) (Taylor et al., 2004). Since then, one bipolar depression study (Eden Evins et al., 2006) and two premenstrual dysphoric disorder (PMDD) studies (Gianfranco et al., 2011, Nemets et al., 2002) have been published. PMDD is a mood disorder affecting women during the last week of the luteal phase and is classified in the depressive disorders section in the Diagnostic and Statistical Manual of Mental Disorders 5 in the same way as major depressive disorder (MDD) (Epperson et al., 2012). Therefore, we conducted an updated meta-analysis of inositol for the treatment of depressed patients (seven studies, n = 242). Moreover, the medications used for anxiety disorders, such as obsessive–compulsive disorder (OCD), generalized anxiety disorder, panic disorder, and posttraumatic stress disorder, are usually antidepressants. It has also been suggested that anxiety disorders and depression share some common pathological mechanisms (Boulenger Received 1 June 2013 Accepted 16 October 2013
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et al., 1997), such as abnormalities in serotonin and glutamate neural transmission. Therefore, we also performed a meta-analysis regardingefficacy of inositol in anxiety disorders. METHODS This meta-analysis was performed according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 (Moher et al., 2009). Inclusion criteria, search strategy, data extraction, and outcome measures Included in this study were randomized control trials (RCTs) using inositol for depressed patients. To identify relevant studies, PubMed, Cochrane Library databases, and PsycINFO citations were searched to 14 August 2013, using the keywords “inositol,” AND “randomized,” “random,” OR “randomly,” AND “major depressive disorder,” “major depression,” “premenstrual dysphoric disorder,” “bipolar disorder,” “mixed,” “bipolar depression,” “anxiety disorder,” “generalized anxiety disorder,” “social anxiety disorder,” “panic disorder,” “posttraumatic stress disorder,” “phobia,” OR “obsessive–compulsive disorder”. Three of the authors of this review (T. M., T. K., and Y. M.) scrutinized the inclusion and exclusion criteria of the studies identified. When the data required for the meta-analysis were missing, the first and/or corresponding authors were contacted for additional information (including endpoint scores). The aforementioned three authors independently extracted, checked, and entered the data into REVIEW MANAGER; (Review Manager version 5.0, Cochrane Collaboration, http://ims.cochrane.org/revman). Data synthesis and statistical analysis We included outcome measures of at least two studies for each outcome measure. The primary outcome measure for efficacy was response rate (using the definition of responder on the basis of the original study). Efficacy was calculated as a ≥50% reduction in the 17item Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960) total score and much improved or very much improved in the Clinical Global Impression-Improvement Scale (CGI-I) (Guy and Bonato, 1970) from two studies (Chengappa et al., 2000, Eden Evins et al., 2006), a reduction of 15 or more points on the 24-item HAM-D total score from one study (Levine et al., 1995), and a ≥50% reduction in the 24-item HAM-D total score and a decrease of 15 or more points on the 24-item HAM-D total score from one study (Levine et al., 1999). The secondary outcome measures also included HAM-D total scores Copyright © 2013 John Wiley & Sons, Ltd.
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using a change of 17 items in the HAM-D total scores from baseline to endpoint from two studies (Chengappa et al., 2000, Eden Evins et al., 2006), a change of 24 items in the HAM-D total scores from baseline to endpoint from one study (Nemets et al., 2002), a 24-item HAM-D total endpoint total score from three studies (Levine et al., 1995, Levine et al., 1999, Nemets et al., 1999), and a HAM-D total endpoint total score from one study (Gianfranco et al., 2011). Other secondary outcome measures included the Yale–Brown Obsessive Compulsive Scale (Goodman et al., 1989) total endpoint total scores from two studies (Fux et al., 1999, Fux et al., 1996) and the Hamilton Anxiety Rating Scale (Hamilton, 1959) total endpoint total scores from two studies (Fux et al., 1996, Kaplan et al., 1996). We asked the author about detailed information of the HAM-D, but the author did not respond to our query. Other outcome measures were discontinuation because of all-causes, side effects, and suicidal ideation and worsening psychiatric symptoms. In addition, we pooled the data for side effects. We based the analyses on intent-to-treat (ITT) or modified ITT data (i.e., at least one dose or at least one follow-up assessment). The data of one crossover study were not excluded to obtain as much information as possible. The meta-analysis was performed using REVIEW MANAGER version 5.1 for Windows (REVIEW MANAGER version 5.1, Cochrane Collaboration, http:// ims.cochrane.org/revman). To combine studies, the conservative random effects model by DerSimonian and Laird (DerSimonian and Laird, 1986) was used for all cases. This random effects model was chosen because the underlying effect might have differed across studies and populations, which are typically heterogeneous. The relative risk (RR) was estimated along with its 95% confidence interval (CI). For continuous data, standardized mean difference (SMD) was used, combining the effect size (Hedges’ g) data. We explored study heterogeneity using the chisquared test of homogeneity (p < 0.05), together with the I2 statistic. I2 values of 50% or higher reflect considerable heterogeneity (Higgins et al., 2003). In cases of I2 values >50% for response rate and HAMD, we planned to conduct sensitivity analyses to determine the reasons for the heterogeneity. However, no significant heterogeneity for the primary outcome measures was found. Funnel plots were inspected visually to assess the possibility of publication bias. RESULTS Study characteristics A search using the key words yielded 149 references. We excluded 96 duplicate studies across the three Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
inositol and depression and anxiety disorders
databases and 27 studies on the basis of the title or abstract review (Figure 1). Seven RCTs comparing inositol with placebo (total n = 242) in depression were identified (Chengappa et al., 2000, Eden Evins et al., 2006, Gianfranco et al., 2011, Levine et al., 1995, Levine et al., 1999, Nemets et al., 1999, Nemets et al., 2002). These included two bipolar depression studies (Chengappa et al., 2000, Eden Evins et al., 2006), one bipolar depression and MDD study (Levine, Barak, 1995), two MDD studies (Levine et al., 1999, Nemets et al., 1999), and two PMDD studies (Gianfranco et al., 2011, Nemets et al., 2002). Four RCTs comparing inositol with placebo (total n = 70) in anxiety disorders were identified (Benjamin et al., 1995b, Fux et al., 1999, Fux et al., 1996Kaplan et al., 1996). These included two OCD studies (Fux et al., 1999, Fux et al., 1996), one panic disorder study (Benjamin et al., 1995b), and one posttraumatic stress disorder study (Kaplan et al., 1996). Two bipolar depression studies and two MDD studies used inositol as an add-on therapy. The other depression studies compared inositol with placebo. One OCD study used inositol as an add-on therapy. The duration of studies, except for the PMDD studies, was 4–8 weeks, with three studies lasting 4 weeks, one study lasting 6 weeks, and one study lasting 8 weeks. The duration
Figure 1.
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of the two PMDD studies was six menstrual cycles. All the studies were double-blinded RCTs. Sample sizes ranged from 12 to 71 patients. One of the 11 studies was sponsored by the pharmaceutical industry (Gianfranco et al., 2011), and all studies were published in English. Eight of the eleven studies were conducted in Israel, and the remaining three studies were conducted in the United States. The characteristics of the studies are shown in Table 1. Meta-analysis results Depression. Inositol was marginally superior to placebo in response rate (RR = 0.72, 95% CI = 0.52–1.01, p = 0.06, I2 = 0; four studies, n = 96) (Figure 2). We did not find any significant differences among subgroups (I2 = 0, p = 0.49). No statistically significant effects of inositol on depressive symptoms scales were reported (SMD = 0.35, p = 0.22; seven studies, n = 188) (Figure 3). Inositol showed a trend towards superior efficacy of depressive symptoms over placebo in patients with PMDD (SMD = 1.15, p = 0.07; two studies, n = 58) (Figure 3). Visual inspection of the funnel plot for primary outcomes in inositol versus placebo RCTs did not suggest the presence of publication bias. Although there was no significant heterogeneity in the response rate between both treatment groups, we
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram
Copyright © 2013 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
Copyright © 2013 John Wiley & Sons, Ltd.
Eden Evins et al., 2006 (USA) nonindustry
18
24
39
BD depression (BD I = 94.1%, BD II = 5.9%). 17-item HAM-D ≥ 15. DBPCT
DBPCT BD depression (BD I = 87.5%, BD II = 12.5%). 17-item HAM-D ≥ 15. The ranges of MD levels for inclusion into the study were Li 0.6– 1.2 mEq/l, VAL 50–125 μg/l, and CAR 4–12 μg/l
MDD or BD depression DBPCT (INO: MDD = 69.2%, depression = 30.8%, PBO: MDD = 86.7%, BD depression = 13.3%). Patients had no response to antidepressant treatment
DBPCT
MDD without psychotic features. 24-item HAM-D ≥ 18 on SSRI treatment (FLUV = 150 mg, FLUO = 20 mg, PAR = 20 mg) for ≥3 weeks
42 4 weeks
4 weeks
Duration
DSM-IV
DSM-IV
6 weeks
6 weeks
DSM-III-R 4 weeks
DSM-IV
DSM-IV
Diagnosis
INO = 23.1, PBO = 35.7
Male (%)
45.8 +/ 12.2
INO = 38 +/ 8, PBO = 47 +/ 13
INO = 63.7, PBO = 50.5
64.7
36.4
INO = 23.1, PBO = 60
INO = 49.5 +/ 11, INO = 38.9, PBO = 51.5 +/ 11 PBO = 38.9
INO = 45.9 +/ 5, PBO = 49.6 +/ 5
Age (mean +/ SD)
NR
NR
NR
NR
NR
Race (%)
(Continues)
12 MD = NR (fixed) 9 INO = 5.7–19 (flexible), 17-item MD = NR (fixed) HAM-D: INO = PBO
PBO INO
17-item HAM-D: INO = PBO, 24-item HAM-D: INO = PBO, MADRS: INO = PBO
12 INO = 12 (fixed), MD = NR (fixed)
19
24-item HAM-D: INO > PBO
24-item HAM-D: INO = PBO
24-item HAM-D: INO = PBO
Outcomes
INO
PBO
INO
20 INO = 12 (fixed)
19 SSRI: FLUV = 150, FLUO = 20, or PAR = 20
PBO
INO
18 SSRI: FLUV = 150, FLUO = 20 or PAR = 20 (fixed) 23 INO = 12 (fixed), SSRI: FLUV = 150, FLUO = 20, or PAR = 20
PBO
Dose (dose mg/day)
18 INO = 12 (fixed), SSRI: FLUV = 150, FLUO = 20 or PAR = 20 (fixed)
n
INO
Drug
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BD depression (SSRI + INO versus SSRI + PBO) Chengappa et al., 2000 (USA) nonindustry
Depression (INO versus PBO) Levine et al., 1995 (Israel) nonindustry
Nemets et al., 1999 (Israel) nonindustry
Study design
MDD (one patient DBPCT entered the study diagnosed as MDD, but after later information was rediagnosed as suffering from BD depression)
Patients
36
Total n
Study, patient, and treatment characteristics of included double-blind, randomized, placebo-controlled trials
MDD (SSRI + INO versus SSRI + PBO) Levine et al., 1999 (Israel) nonindustry
Study
Table 1.
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Copyright © 2013 John Wiley & Sons, Ltd.
17
25
13
15
12
71
Total n
DSM-IV
Diagnosis
Six menstrual cycles
Six menstrual cycles
Duration
6 weeks
DBPCT DSM-III-R 4 weeks (crossover)
DBPCT DSM-IV (crossover)
DBPCT DSM-III-R 6 weeks (crossover)
DBPCT DSM-IV (crossover)
DBPCT
Study design
PTSD. Lack of response DBPCT DSM-III-R 4 weeks to previous treatment (crossover) with ADs and other treatment
PD
OCD. Inadequate response to SRI therapy (FLUO = 40–60 mg, FLUV = 200–250 mg, CHL = 150–225 mg)
OCD. Lack of response to previous treatment with clomipramine or SSRIs or side effects with previous treatment
PMDD
PMDD
The ranges of MD levels for inclusion into the study were Li > 0.80 mEq/l or VAL ≥ 50 μg/l
Patients
39.7
35.8 +/ 7
30.3 +/ 9
33.7
35.9 +/ 5
18 and 45 years
Age (mean +/ SD)
61.5
42.9
20.0
38.5
0
0
Male (%)
NR
NR
NR
NR
NR
NR
Race (%)
Dose (dose mg/day)
9 MD = NR (fixed)
n
PBO
INO
PBO
INO
PBO
INO
PBO
INO
PBO
INO = 12 (fixed)
INO = 12 (fixed)
INO = 18 (fixed), SRI = NR (fixed)
INO = 18 (fixed)
myo-INO 37 myo-INO powder = 12 (fixed), myo-INO soft gel capsule = 3.6 (fixed) PBO 34 myo-INO myo-INO = 12 (fixed)
PBO
Drug
IES: INO = PBO, HAM-D: INO = PBO, HAM-A: INO = PBO
Number of attacks: INO > PBO, panic score: INO > PBO, MMPS: INO > PBO
Y-BOX: INO = PBO, HAM-D: INO = PBO, HAM-A: INO = PBO
Y-BOX: INO > PBO, HAM-D: INO = PBO, HAM-A: INO = PBO
24-item HAM-D: myo-INO = PBO
HAM-D: myoINO > PBO
Outcomes
AD, antidepressant; BD, bipolar disorder; CAR, carbamazepine; CHL, clomipramine; DBPCT, double-blind, placebo-controlled trial; DSM, Diagnostic and Statistical Manual of Mental Disorders; FLUO, fluoxetine; FLUV, fluvoxamine; HAM-A:,Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; IES, Impact of Event Scale; INO, inositol; Li, lithium; MADRS, Montgomery–Asberg Depression Rating Scale; MD, mood stabilizer; MDD, major depressive disorder; MMPS, Marks–Matthews Phobia Scale; OCD, obsessive–compulsive disorder; PAR, paroxetine; PBO, placebo; PD, panic disorder; PMDD, premenstrual dysphoric disorder; PTSD, posttraumatic stress disorder; SRI, serotonin reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; VAL, valproate; Y-BOX, Yale–Brown Obsessive Compulsive Scale.
PTSD (INO versus PBO) Kaplan et al., 1996 (Israel) nonindustry
PD (INO versus PBO) Benjamin et al., 1995a, 1995b (Israel) nonindustry
OCD (SRI + INO versus SRI + PBO) Fux et al., 1999 (Israel) nonindustry
OCD (INO versus PBO) Fux et al., 1996 (Israel) nonindustry
Nemets et al., 2002 (Israel) nonindustry
PMDD (INO versus PBO) Gianfranco et al., 2011 (USA) industry
Study
Table 1. (Continued)
inositol and depression and anxiety disorders 59
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Figure 2.
Forest plot of response rate
Figure 3.
Forest plot of Hamilton Depression Rating Scale
Copyright © 2013 John Wiley & Sons, Ltd.
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Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
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found a significant heterogeneity in HAM-D scores (I2 = 70%, p = 0.003). Therefore, we conducted a sensitivity analysis to investigate the confounding factor. We found a significant difference among subgroups (I2 = 55.8%, p = 0.08). Although there were marginal differences in the HAM-D score of “Inositol for Depression” (SMD = 0.71, p = 0.07) and “Inositol for PMDD” (SMD = 1.15, p = 0.07), we found no significant difference in the HAM-D scores of other subgroups. Because only one or two studies were included in each subgroup, we did not conduct more sensitivity analyses. For secondary outcomes, inositol did not outperform placebo regarding discontinuation because of all cause (RR = 1.43, 95% CI = 0.73–2.82, p = 0.30; six studies, n = 230), side effects (RR = 0.69, 95% CI = 0.25–1.93, p = 0.48; six studies, n = 230), and worsening psychiatric symptoms (RR = 1.39, 95% CI = 0.40–4.85, p = 0.61; six studies, n = 230). Because inositol is well tolerated, few side effects were reported. We performed a meta-analysis for side effects using only two individual side effects. Although there were no significant differences in at least one side effect (RR = 0.86, p = 0.63; four studies, n = 142), inositol marginally
Figure 4.
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caused gastrointestinal side effects compared with placebo (RR = 3.26, p = 0.06; six studies, n = 183) (Figure 4). Anxiety disorders. Inositol was not superior to placebo in Yale–Brown Obsessive Compulsive Scale (SMD = 0.15, 95% CI = 0.73 to 0.43, p = 0.60, I2 = 0; two studies, n = 46) and Hamilton Anxiety Rating Scale (SMD = 0.04, 95% CI = 0.51 to 0.58, p = 0.89, I2 = 0; two studies, n = 52). Because there were only four anxiety disorder studies, we did not perform any meta-analysis in anxiety disorders other than the aforementioned meta-analyses. DISCUSSION For this meta-analysis, seven RCTs involving 272 patients were examined. The total number of patients doubled from the previous meta-analysis (four studies, n = 141) on inositol for the treatment of depressed patients. We did not find a significant treatment effect of inositol for depressed patients. However, because the treatment condition and diagnosis among the depression
Forest plot of gastrointestinal upset
Copyright © 2013 John Wiley & Sons, Ltd.
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studies included in the meta-analysis were different, and because these were very small studies included in the meta-analysis, we did not obtain robust evidence that inositol did not have a benefit for the treatment of depression. Moreover, inositol showed a trend towards superior efficacy of depressive symptoms over placebo in patients with PMDD. Moreover, inositol was well tolerated. However, because there were only two PMDD studies included in the meta-analysis, it is necessary to confirm these findings by performing a double-blind, randomized, placebo-controlled, large-sample trial of inositol for the treatment of PMDD. Several studies suggest that the etiology of PMDD relies at least in part on decreases in serum progesterone and estradiol levels; therefore, PMDD has been considered to be a consequence of steroid withdrawal (Schmidt et al., 1998). Additional studies will be needed to clarify whether inositol affects serum progesterone and estradiol levels. To our knowledge, this is the first meta-analysis on the effectiveness and tolerability of inositol in the treatment of anxiety disorders. There were very small studies included in the meta-analysis. We performed the metaanalyses for anxiety disorders in only two outcomes (anxiety and obsessive–compulsive symptoms). Therefore, although we draw the conclusion regarding whether inositol has a benefit for anxiety disorders, inositol does not seem to have a benefit for the treatment of anxiety disorders. However, it was reported that inositol might be more efficacious for the frequency and severity of panic attacks than placebo (Benjamin et al., 1995b). The main limitation of this analysis is the small number of studies that were included. The second limitation is that all studies, with the exception of the PMDD studies, included in this meta-analysis were of short duration (≤8 weeks). Additional long-term efficacy and safety data are needed. The third limitation is that although a funnel plot for primary and secondary outcomes did not suggest the presence of publication bias, the number of studies included in the meta-analysis was too small to allow any reasonable interpretation of funnel plots.
CONCLUSION Our results suggest that while inositol may offer a beneficial effect compared with placebo on depressed patients, especially those with PMDD, inositol seems to not provide a benefit for the treatment of anxiety disorders. Given that a small number of studies were included in this meta-analysis, the results should be treated with caution. Copyright © 2013 John Wiley & Sons, Ltd.
ET AL.
CONFLICTS OF INTEREST Dr. Mukai and Dr. Matsuda have nothing to disclose. Dr. Mukai, Dr. Kishi, Dr. Matsuda, and Dr. Iwata declare that they have no direct conflicts of interest or grant support that is directly related to the content of the study. ACKNOWLEDGEMENTS Dr. Kishi has received speaker’s honoraria from Abbott, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Yoshitomi, Otsuka, Meiji, Shionogi, Mitsubishi-Tanabe, Janssen, Novartis, and Pfizer. Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, and Pfizer. We thank Dr. Joseph Levine (Ben Gurion University of the Negev) and Dr. Boris Nemets (Ben Gurion University of the Negev) for providing information from their studies.
AUTHOR CONTRIBUTIONS Dr. Mukai and Dr. Kishi had full access to all of the data in the study and bear responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kishi. Analysis and interpretation of data and statistical analysis: Mukai and Kishi. Acquisition of data: Mukai, Kishi and Matsuda. Drafting of the manuscript: Mukai, Kishi and Iwata. Study supervision: Iwata. REFERENCES Albert PR, Benkelfat C. 2013. The neurobiology of depression—revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies. Philos Trans R Soc Lond B Biol Sci 368: 20120535. Albert PR, Benkelfat C, Descarries L. 2012. The Neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc London [Biol] 367: 2378–2381. Barkai AI, Dunner DL, Gross HA, Mayo P, Fieve RR. 1978. Reduced myoinositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psychiatry 13: 65–72. Benjamin J, Agam G, Levine J, Bersudsky Y, Kofman O, Belmaker RH. 1995a. Inositol treatment in psychiatry. Psychopharmacol Bull 31: 167–175. Benjamin J, Levine J, Fux M, Aviv A, Levy D, Belmaker RH. 1995b. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152: 1084–1086. Boulenger JP, Fournier M, Rosales D, Lavallee YJ. 1997. Mixed anxiety and depression: from theory to practice. J Clin Psychiatry 58(Suppl 8): 27–34. Camfield DA, Sarris J, Berk M. 2011. Nutraceuticals in the treatment of obsessive–compulsive disorder (OCD): a review of mechanistic and clinical evidence. Prog Neuropsychopharmacol Biol Psychiatry 35: 887–895. Chengappa KN, Levine J, Gershon S, Mallinger AG, Hardan A, Vagnucci A, et al. 2000. Inositol as an add-on treatment for bipolar depression. Bipolar disorders 2: 47–55.
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Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
A meta-analysis of inositol for depression and anxiety disorders Tomohiko Mukai†, Taro Kishi*,†, Yuki Matsuda and Nakao Iwata Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan
Objective This study is a meta-analysis of inositol as a treatment for depression and anxiety disorders. Methods PubMed, Cochrane Library database, and PsycINFO were searched up to 14 August 2013. A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials (RCTs) were conducted comparing inositol for depressed or anxiety disorder patients. Results Seven RCTs in depression (two bipolar depression studies, one bipolar depression and major depressive disorder (MDD) study, two MDD studies, and two premenstrual dysphoric disorder (PMDD) studies) (n = 242) were identified. Four RCTs in anxiety disorders (two obsessive–compulsive disorder studies, one panic disorder study, and one posttraumatic stress disorder study) (n = 70) were also identified. There were no statistically significant effects of inositol on depressive, anxiety, and obsessive–compulsive symptoms and discontinuation (all-cause, side effects, and worsening psychiatric symptoms). However, inositol had marginally more responders in depression than placebo (p = 0.06), and inositol showed a trend towards superior efficacy for depressive symptoms in patients with PMDD (p = 0.07). Inositol marginally caused gastrointestinal upset compared with placebo (p = 0.06). Conclusions Our results suggest that inositol may be beneficial for depressed patients, especially those with PMDD. The main limitation of this report is that a small number of studies were included in this meta-analysis. Copyright © 2013 John Wiley & Sons, Ltd. key words—inositol; major depressive disorder; bipolar depression; premenstrual dysphoric disorder; anxiety disorder; meta-analysis
INTRODUCTION Inositol has been reported to be effective for the treatment of depressed patients (Benjamin et al., 1995a). Inositol is naturally found in a variety of foods and is a vitamin-like substance that is present in all animal tissues (the highest concentrations are found in the heart and brain). Inositol is a constituent of the intracellular phosphatidyl inositol second messenger system, which is linked to various neurotransmitter receptors, such as serotonin, dopamine, and glutamate receptor, thereby altering brain neurotransmitters including serotonin level (Benjamin et al., 1995a, Camfield et al., 2011). This accumulated evidence supports the indoleamine hypothesis of depression, which suggests that major depression results from inefficient serotonin or deficient amounts of available serotonin (Albert and Benkelfat, 2013, Albert et al., 2012). In addition, several lines of evidence implicate abnormalities in glutamate neural transmission in the pathophysiology of depression (i.e., the glutamate hypothesis of depression). When postmortem brain tissues were examined from depressed patients, low *Correspondence to: T. Kishi, Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Aichi 470-1192, Japan. E-mail: [email protected] † These authors contributed equally to this work.
Copyright © 2013 John Wiley & Sons, Ltd.
inositol levels were found in the frontal cortex (Coupland et al., 2005, Shimon et al., 1997). In addition, Barkai and colleagues found reduced levels of inositol in the cerebrospinal fluid of depressed patients (Barkai et al., 1978). Taylor and colleagues reported that inositol did not show clear evidence of a therapeutic benefit in depressed patients (four studies, n = 141) (Taylor et al., 2004). Since then, one bipolar depression study (Eden Evins et al., 2006) and two premenstrual dysphoric disorder (PMDD) studies (Gianfranco et al., 2011, Nemets et al., 2002) have been published. PMDD is a mood disorder affecting women during the last week of the luteal phase and is classified in the depressive disorders section in the Diagnostic and Statistical Manual of Mental Disorders 5 in the same way as major depressive disorder (MDD) (Epperson et al., 2012). Therefore, we conducted an updated meta-analysis of inositol for the treatment of depressed patients (seven studies, n = 242). Moreover, the medications used for anxiety disorders, such as obsessive–compulsive disorder (OCD), generalized anxiety disorder, panic disorder, and posttraumatic stress disorder, are usually antidepressants. It has also been suggested that anxiety disorders and depression share some common pathological mechanisms (Boulenger Received 1 June 2013 Accepted 16 October 2013
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et al., 1997), such as abnormalities in serotonin and glutamate neural transmission. Therefore, we also performed a meta-analysis regardingefficacy of inositol in anxiety disorders. METHODS This meta-analysis was performed according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 (Moher et al., 2009). Inclusion criteria, search strategy, data extraction, and outcome measures Included in this study were randomized control trials (RCTs) using inositol for depressed patients. To identify relevant studies, PubMed, Cochrane Library databases, and PsycINFO citations were searched to 14 August 2013, using the keywords “inositol,” AND “randomized,” “random,” OR “randomly,” AND “major depressive disorder,” “major depression,” “premenstrual dysphoric disorder,” “bipolar disorder,” “mixed,” “bipolar depression,” “anxiety disorder,” “generalized anxiety disorder,” “social anxiety disorder,” “panic disorder,” “posttraumatic stress disorder,” “phobia,” OR “obsessive–compulsive disorder”. Three of the authors of this review (T. M., T. K., and Y. M.) scrutinized the inclusion and exclusion criteria of the studies identified. When the data required for the meta-analysis were missing, the first and/or corresponding authors were contacted for additional information (including endpoint scores). The aforementioned three authors independently extracted, checked, and entered the data into REVIEW MANAGER; (Review Manager version 5.0, Cochrane Collaboration, http://ims.cochrane.org/revman). Data synthesis and statistical analysis We included outcome measures of at least two studies for each outcome measure. The primary outcome measure for efficacy was response rate (using the definition of responder on the basis of the original study). Efficacy was calculated as a ≥50% reduction in the 17item Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960) total score and much improved or very much improved in the Clinical Global Impression-Improvement Scale (CGI-I) (Guy and Bonato, 1970) from two studies (Chengappa et al., 2000, Eden Evins et al., 2006), a reduction of 15 or more points on the 24-item HAM-D total score from one study (Levine et al., 1995), and a ≥50% reduction in the 24-item HAM-D total score and a decrease of 15 or more points on the 24-item HAM-D total score from one study (Levine et al., 1999). The secondary outcome measures also included HAM-D total scores Copyright © 2013 John Wiley & Sons, Ltd.
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using a change of 17 items in the HAM-D total scores from baseline to endpoint from two studies (Chengappa et al., 2000, Eden Evins et al., 2006), a change of 24 items in the HAM-D total scores from baseline to endpoint from one study (Nemets et al., 2002), a 24-item HAM-D total endpoint total score from three studies (Levine et al., 1995, Levine et al., 1999, Nemets et al., 1999), and a HAM-D total endpoint total score from one study (Gianfranco et al., 2011). Other secondary outcome measures included the Yale–Brown Obsessive Compulsive Scale (Goodman et al., 1989) total endpoint total scores from two studies (Fux et al., 1999, Fux et al., 1996) and the Hamilton Anxiety Rating Scale (Hamilton, 1959) total endpoint total scores from two studies (Fux et al., 1996, Kaplan et al., 1996). We asked the author about detailed information of the HAM-D, but the author did not respond to our query. Other outcome measures were discontinuation because of all-causes, side effects, and suicidal ideation and worsening psychiatric symptoms. In addition, we pooled the data for side effects. We based the analyses on intent-to-treat (ITT) or modified ITT data (i.e., at least one dose or at least one follow-up assessment). The data of one crossover study were not excluded to obtain as much information as possible. The meta-analysis was performed using REVIEW MANAGER version 5.1 for Windows (REVIEW MANAGER version 5.1, Cochrane Collaboration, http:// ims.cochrane.org/revman). To combine studies, the conservative random effects model by DerSimonian and Laird (DerSimonian and Laird, 1986) was used for all cases. This random effects model was chosen because the underlying effect might have differed across studies and populations, which are typically heterogeneous. The relative risk (RR) was estimated along with its 95% confidence interval (CI). For continuous data, standardized mean difference (SMD) was used, combining the effect size (Hedges’ g) data. We explored study heterogeneity using the chisquared test of homogeneity (p < 0.05), together with the I2 statistic. I2 values of 50% or higher reflect considerable heterogeneity (Higgins et al., 2003). In cases of I2 values >50% for response rate and HAMD, we planned to conduct sensitivity analyses to determine the reasons for the heterogeneity. However, no significant heterogeneity for the primary outcome measures was found. Funnel plots were inspected visually to assess the possibility of publication bias. RESULTS Study characteristics A search using the key words yielded 149 references. We excluded 96 duplicate studies across the three Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
inositol and depression and anxiety disorders
databases and 27 studies on the basis of the title or abstract review (Figure 1). Seven RCTs comparing inositol with placebo (total n = 242) in depression were identified (Chengappa et al., 2000, Eden Evins et al., 2006, Gianfranco et al., 2011, Levine et al., 1995, Levine et al., 1999, Nemets et al., 1999, Nemets et al., 2002). These included two bipolar depression studies (Chengappa et al., 2000, Eden Evins et al., 2006), one bipolar depression and MDD study (Levine, Barak, 1995), two MDD studies (Levine et al., 1999, Nemets et al., 1999), and two PMDD studies (Gianfranco et al., 2011, Nemets et al., 2002). Four RCTs comparing inositol with placebo (total n = 70) in anxiety disorders were identified (Benjamin et al., 1995b, Fux et al., 1999, Fux et al., 1996Kaplan et al., 1996). These included two OCD studies (Fux et al., 1999, Fux et al., 1996), one panic disorder study (Benjamin et al., 1995b), and one posttraumatic stress disorder study (Kaplan et al., 1996). Two bipolar depression studies and two MDD studies used inositol as an add-on therapy. The other depression studies compared inositol with placebo. One OCD study used inositol as an add-on therapy. The duration of studies, except for the PMDD studies, was 4–8 weeks, with three studies lasting 4 weeks, one study lasting 6 weeks, and one study lasting 8 weeks. The duration
Figure 1.
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of the two PMDD studies was six menstrual cycles. All the studies were double-blinded RCTs. Sample sizes ranged from 12 to 71 patients. One of the 11 studies was sponsored by the pharmaceutical industry (Gianfranco et al., 2011), and all studies were published in English. Eight of the eleven studies were conducted in Israel, and the remaining three studies were conducted in the United States. The characteristics of the studies are shown in Table 1. Meta-analysis results Depression. Inositol was marginally superior to placebo in response rate (RR = 0.72, 95% CI = 0.52–1.01, p = 0.06, I2 = 0; four studies, n = 96) (Figure 2). We did not find any significant differences among subgroups (I2 = 0, p = 0.49). No statistically significant effects of inositol on depressive symptoms scales were reported (SMD = 0.35, p = 0.22; seven studies, n = 188) (Figure 3). Inositol showed a trend towards superior efficacy of depressive symptoms over placebo in patients with PMDD (SMD = 1.15, p = 0.07; two studies, n = 58) (Figure 3). Visual inspection of the funnel plot for primary outcomes in inositol versus placebo RCTs did not suggest the presence of publication bias. Although there was no significant heterogeneity in the response rate between both treatment groups, we
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram
Copyright © 2013 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
Copyright © 2013 John Wiley & Sons, Ltd.
Eden Evins et al., 2006 (USA) nonindustry
18
24
39
BD depression (BD I = 94.1%, BD II = 5.9%). 17-item HAM-D ≥ 15. DBPCT
DBPCT BD depression (BD I = 87.5%, BD II = 12.5%). 17-item HAM-D ≥ 15. The ranges of MD levels for inclusion into the study were Li 0.6– 1.2 mEq/l, VAL 50–125 μg/l, and CAR 4–12 μg/l
MDD or BD depression DBPCT (INO: MDD = 69.2%, depression = 30.8%, PBO: MDD = 86.7%, BD depression = 13.3%). Patients had no response to antidepressant treatment
DBPCT
MDD without psychotic features. 24-item HAM-D ≥ 18 on SSRI treatment (FLUV = 150 mg, FLUO = 20 mg, PAR = 20 mg) for ≥3 weeks
42 4 weeks
4 weeks
Duration
DSM-IV
DSM-IV
6 weeks
6 weeks
DSM-III-R 4 weeks
DSM-IV
DSM-IV
Diagnosis
INO = 23.1, PBO = 35.7
Male (%)
45.8 +/ 12.2
INO = 38 +/ 8, PBO = 47 +/ 13
INO = 63.7, PBO = 50.5
64.7
36.4
INO = 23.1, PBO = 60
INO = 49.5 +/ 11, INO = 38.9, PBO = 51.5 +/ 11 PBO = 38.9
INO = 45.9 +/ 5, PBO = 49.6 +/ 5
Age (mean +/ SD)
NR
NR
NR
NR
NR
Race (%)
(Continues)
12 MD = NR (fixed) 9 INO = 5.7–19 (flexible), 17-item MD = NR (fixed) HAM-D: INO = PBO
PBO INO
17-item HAM-D: INO = PBO, 24-item HAM-D: INO = PBO, MADRS: INO = PBO
12 INO = 12 (fixed), MD = NR (fixed)
19
24-item HAM-D: INO > PBO
24-item HAM-D: INO = PBO
24-item HAM-D: INO = PBO
Outcomes
INO
PBO
INO
20 INO = 12 (fixed)
19 SSRI: FLUV = 150, FLUO = 20, or PAR = 20
PBO
INO
18 SSRI: FLUV = 150, FLUO = 20 or PAR = 20 (fixed) 23 INO = 12 (fixed), SSRI: FLUV = 150, FLUO = 20, or PAR = 20
PBO
Dose (dose mg/day)
18 INO = 12 (fixed), SSRI: FLUV = 150, FLUO = 20 or PAR = 20 (fixed)
n
INO
Drug
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BD depression (SSRI + INO versus SSRI + PBO) Chengappa et al., 2000 (USA) nonindustry
Depression (INO versus PBO) Levine et al., 1995 (Israel) nonindustry
Nemets et al., 1999 (Israel) nonindustry
Study design
MDD (one patient DBPCT entered the study diagnosed as MDD, but after later information was rediagnosed as suffering from BD depression)
Patients
36
Total n
Study, patient, and treatment characteristics of included double-blind, randomized, placebo-controlled trials
MDD (SSRI + INO versus SSRI + PBO) Levine et al., 1999 (Israel) nonindustry
Study
Table 1.
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Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
Copyright © 2013 John Wiley & Sons, Ltd.
17
25
13
15
12
71
Total n
DSM-IV
Diagnosis
Six menstrual cycles
Six menstrual cycles
Duration
6 weeks
DBPCT DSM-III-R 4 weeks (crossover)
DBPCT DSM-IV (crossover)
DBPCT DSM-III-R 6 weeks (crossover)
DBPCT DSM-IV (crossover)
DBPCT
Study design
PTSD. Lack of response DBPCT DSM-III-R 4 weeks to previous treatment (crossover) with ADs and other treatment
PD
OCD. Inadequate response to SRI therapy (FLUO = 40–60 mg, FLUV = 200–250 mg, CHL = 150–225 mg)
OCD. Lack of response to previous treatment with clomipramine or SSRIs or side effects with previous treatment
PMDD
PMDD
The ranges of MD levels for inclusion into the study were Li > 0.80 mEq/l or VAL ≥ 50 μg/l
Patients
39.7
35.8 +/ 7
30.3 +/ 9
33.7
35.9 +/ 5
18 and 45 years
Age (mean +/ SD)
61.5
42.9
20.0
38.5
0
0
Male (%)
NR
NR
NR
NR
NR
NR
Race (%)
Dose (dose mg/day)
9 MD = NR (fixed)
n
PBO
INO
PBO
INO
PBO
INO
PBO
INO
PBO
INO = 12 (fixed)
INO = 12 (fixed)
INO = 18 (fixed), SRI = NR (fixed)
INO = 18 (fixed)
myo-INO 37 myo-INO powder = 12 (fixed), myo-INO soft gel capsule = 3.6 (fixed) PBO 34 myo-INO myo-INO = 12 (fixed)
PBO
Drug
IES: INO = PBO, HAM-D: INO = PBO, HAM-A: INO = PBO
Number of attacks: INO > PBO, panic score: INO > PBO, MMPS: INO > PBO
Y-BOX: INO = PBO, HAM-D: INO = PBO, HAM-A: INO = PBO
Y-BOX: INO > PBO, HAM-D: INO = PBO, HAM-A: INO = PBO
24-item HAM-D: myo-INO = PBO
HAM-D: myoINO > PBO
Outcomes
AD, antidepressant; BD, bipolar disorder; CAR, carbamazepine; CHL, clomipramine; DBPCT, double-blind, placebo-controlled trial; DSM, Diagnostic and Statistical Manual of Mental Disorders; FLUO, fluoxetine; FLUV, fluvoxamine; HAM-A:,Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; IES, Impact of Event Scale; INO, inositol; Li, lithium; MADRS, Montgomery–Asberg Depression Rating Scale; MD, mood stabilizer; MDD, major depressive disorder; MMPS, Marks–Matthews Phobia Scale; OCD, obsessive–compulsive disorder; PAR, paroxetine; PBO, placebo; PD, panic disorder; PMDD, premenstrual dysphoric disorder; PTSD, posttraumatic stress disorder; SRI, serotonin reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; VAL, valproate; Y-BOX, Yale–Brown Obsessive Compulsive Scale.
PTSD (INO versus PBO) Kaplan et al., 1996 (Israel) nonindustry
PD (INO versus PBO) Benjamin et al., 1995a, 1995b (Israel) nonindustry
OCD (SRI + INO versus SRI + PBO) Fux et al., 1999 (Israel) nonindustry
OCD (INO versus PBO) Fux et al., 1996 (Israel) nonindustry
Nemets et al., 2002 (Israel) nonindustry
PMDD (INO versus PBO) Gianfranco et al., 2011 (USA) industry
Study
Table 1. (Continued)
inositol and depression and anxiety disorders 59
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Figure 2.
Forest plot of response rate
Figure 3.
Forest plot of Hamilton Depression Rating Scale
Copyright © 2013 John Wiley & Sons, Ltd.
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Hum. Psychopharmacol Clin Exp 2014; 29: 55–63. DOI: 10.1002/hup
inositol and depression and anxiety disorders
found a significant heterogeneity in HAM-D scores (I2 = 70%, p = 0.003). Therefore, we conducted a sensitivity analysis to investigate the confounding factor. We found a significant difference among subgroups (I2 = 55.8%, p = 0.08). Although there were marginal differences in the HAM-D score of “Inositol for Depression” (SMD = 0.71, p = 0.07) and “Inositol for PMDD” (SMD = 1.15, p = 0.07), we found no significant difference in the HAM-D scores of other subgroups. Because only one or two studies were included in each subgroup, we did not conduct more sensitivity analyses. For secondary outcomes, inositol did not outperform placebo regarding discontinuation because of all cause (RR = 1.43, 95% CI = 0.73–2.82, p = 0.30; six studies, n = 230), side effects (RR = 0.69, 95% CI = 0.25–1.93, p = 0.48; six studies, n = 230), and worsening psychiatric symptoms (RR = 1.39, 95% CI = 0.40–4.85, p = 0.61; six studies, n = 230). Because inositol is well tolerated, few side effects were reported. We performed a meta-analysis for side effects using only two individual side effects. Although there were no significant differences in at least one side effect (RR = 0.86, p = 0.63; four studies, n = 142), inositol marginally
Figure 4.
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caused gastrointestinal side effects compared with placebo (RR = 3.26, p = 0.06; six studies, n = 183) (Figure 4). Anxiety disorders. Inositol was not superior to placebo in Yale–Brown Obsessive Compulsive Scale (SMD = 0.15, 95% CI = 0.73 to 0.43, p = 0.60, I2 = 0; two studies, n = 46) and Hamilton Anxiety Rating Scale (SMD = 0.04, 95% CI = 0.51 to 0.58, p = 0.89, I2 = 0; two studies, n = 52). Because there were only four anxiety disorder studies, we did not perform any meta-analysis in anxiety disorders other than the aforementioned meta-analyses. DISCUSSION For this meta-analysis, seven RCTs involving 272 patients were examined. The total number of patients doubled from the previous meta-analysis (four studies, n = 141) on inositol for the treatment of depressed patients. We did not find a significant treatment effect of inositol for depressed patients. However, because the treatment condition and diagnosis among the depression
Forest plot of gastrointestinal upset
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studies included in the meta-analysis were different, and because these were very small studies included in the meta-analysis, we did not obtain robust evidence that inositol did not have a benefit for the treatment of depression. Moreover, inositol showed a trend towards superior efficacy of depressive symptoms over placebo in patients with PMDD. Moreover, inositol was well tolerated. However, because there were only two PMDD studies included in the meta-analysis, it is necessary to confirm these findings by performing a double-blind, randomized, placebo-controlled, large-sample trial of inositol for the treatment of PMDD. Several studies suggest that the etiology of PMDD relies at least in part on decreases in serum progesterone and estradiol levels; therefore, PMDD has been considered to be a consequence of steroid withdrawal (Schmidt et al., 1998). Additional studies will be needed to clarify whether inositol affects serum progesterone and estradiol levels. To our knowledge, this is the first meta-analysis on the effectiveness and tolerability of inositol in the treatment of anxiety disorders. There were very small studies included in the meta-analysis. We performed the metaanalyses for anxiety disorders in only two outcomes (anxiety and obsessive–compulsive symptoms). Therefore, although we draw the conclusion regarding whether inositol has a benefit for anxiety disorders, inositol does not seem to have a benefit for the treatment of anxiety disorders. However, it was reported that inositol might be more efficacious for the frequency and severity of panic attacks than placebo (Benjamin et al., 1995b). The main limitation of this analysis is the small number of studies that were included. The second limitation is that all studies, with the exception of the PMDD studies, included in this meta-analysis were of short duration (≤8 weeks). Additional long-term efficacy and safety data are needed. The third limitation is that although a funnel plot for primary and secondary outcomes did not suggest the presence of publication bias, the number of studies included in the meta-analysis was too small to allow any reasonable interpretation of funnel plots.
CONCLUSION Our results suggest that while inositol may offer a beneficial effect compared with placebo on depressed patients, especially those with PMDD, inositol seems to not provide a benefit for the treatment of anxiety disorders. Given that a small number of studies were included in this meta-analysis, the results should be treated with caution. Copyright © 2013 John Wiley & Sons, Ltd.
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CONFLICTS OF INTEREST Dr. Mukai and Dr. Matsuda have nothing to disclose. Dr. Mukai, Dr. Kishi, Dr. Matsuda, and Dr. Iwata declare that they have no direct conflicts of interest or grant support that is directly related to the content of the study. ACKNOWLEDGEMENTS Dr. Kishi has received speaker’s honoraria from Abbott, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Yoshitomi, Otsuka, Meiji, Shionogi, Mitsubishi-Tanabe, Janssen, Novartis, and Pfizer. Dr. Iwata has received speaker’s honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, and Pfizer. We thank Dr. Joseph Levine (Ben Gurion University of the Negev) and Dr. Boris Nemets (Ben Gurion University of the Negev) for providing information from their studies.
AUTHOR CONTRIBUTIONS Dr. Mukai and Dr. Kishi had full access to all of the data in the study and bear responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kishi. Analysis and interpretation of data and statistical analysis: Mukai and Kishi. Acquisition of data: Mukai, Kishi and Matsuda. Drafting of the manuscript: Mukai, Kishi and Iwata. Study supervision: Iwata. REFERENCES Albert PR, Benkelfat C. 2013. The neurobiology of depression—revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies. Philos Trans R Soc Lond B Biol Sci 368: 20120535. Albert PR, Benkelfat C, Descarries L. 2012. The Neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc London [Biol] 367: 2378–2381. Barkai AI, Dunner DL, Gross HA, Mayo P, Fieve RR. 1978. Reduced myoinositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psychiatry 13: 65–72. Benjamin J, Agam G, Levine J, Bersudsky Y, Kofman O, Belmaker RH. 1995a. Inositol treatment in psychiatry. Psychopharmacol Bull 31: 167–175. Benjamin J, Levine J, Fux M, Aviv A, Levy D, Belmaker RH. 1995b. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152: 1084–1086. Boulenger JP, Fournier M, Rosales D, Lavallee YJ. 1997. Mixed anxiety and depression: from theory to practice. J Clin Psychiatry 58(Suppl 8): 27–34. Camfield DA, Sarris J, Berk M. 2011. Nutraceuticals in the treatment of obsessive–compulsive disorder (OCD): a review of mechanistic and clinical evidence. Prog Neuropsychopharmacol Biol Psychiatry 35: 887–895. Chengappa KN, Levine J, Gershon S, Mallinger AG, Hardan A, Vagnucci A, et al. 2000. Inositol as an add-on treatment for bipolar depression. Bipolar disorders 2: 47–55.
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